Note: Descriptions are shown in the official language in which they were submitted.
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USE OF DRONEDARONE FOR THE PREPARATION OF A DRUG FOR USE IN THE
MANAGEMENT OF THE RISK OF LIVER INJURY
The present invention relates to the use of dronedarone for the preparation of
a drug
The present invention relates to the use of dronedarone for the preparation of
a drug
for use in a safe way in patients with cardiovascular history.
The instant invention also relates to a method of managing the risk of liver
injury in
patients receiving treatment with dronedarone or pharmaceutically acceptable
salts
thereof.
The instant invention also relates to a method of reducing the risk of liver
injury in
patients receiving treatment with dronedarone or pharmaceutically acceptable
salts
thereof.
2-n-Butyl-3-[4-(3-di-n-butylaminopropoxy)benzoy1]-5-
methylsulphonamidobenzofuran,
or dronedarone, and pharmaceutically acceptable salts thereof, in particular
its
hydrochloride salts, are described in European Patent EP 0 471 609 B1.
Moreover, dronedarone is effective in maintaining sinus rhythm in patients
presenting
atrial fibrillation or atrial flutter.
The applicant has clinically proven that dronedarone significantly reduces
cardiovascular hospitalizations and/or mortality in patients having a history
of atrial
fibrillation (AF) or of atrial flutter (AFL) in a safe and effective way. In
USA,
Dronedarone is indicated to reduce the risk of cardiovascular hospitalization
in patients
safe and effective way, with a method to manage the risk of liver injury in
patients
receiving treatment with dronedarone or pharmaceutically acceptable salts
thereof by
performing the following steps:
a) performing liver function tests prior to treatment with dronedarone,
35 b) monitoring liver function monthly for six months, at months 9 and 12,
and
periodically thereafter,
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c) if alanine aminotransferase (ALT) levels are elevated higher than three
times
the upper limit of normal (ULN), re-measuring levels,
d) if confirmed to be greater than three times the upper limit of normal,
withdrawing administration of dronedarone,
e) continuing close observation until normalization of ALT and,
f) investigating the probable cause, including those related to underlying
cardiac
conditions.
The invention also relates to the regimen to administrate dronedarone to
patients in a
1 0 safe and effective way, with a method to manage the risk of liver
injury in patients
receiving treatment with dronedarone or pharmaceutically acceptable salts
thereof by
performing the following steps:
a) performing liver function tests prior to treatment with dronedarone,
b) monitoring liver function monthly for six months, at months 9 and 12, and
periodically thereafter,
c) if alanine aminotransferase (ALT) levels are elevated higher than three
times
the upper limit of normal (ULN), re-measuring levels for example within 48 to
72
hours,
d) if confirmed to be greater than three times the upper limit of normal,
2 0 withdrawing administration of dronedarone,
e) continuing close observation until normalization of ALT and,
f) investigating the probable cause, including those related to underlying
cardiac
conditions.
Mention may be made that "performing liver function tests prior to treatment
with
dronedarone" means obtaining a blood sample from the patient prior to
treatment with
dronedarone then performing liver function tests prior to treatment with
dronedarone.
Mention may be made that "monitoring liver function monthly for six months, at
months
9 and 12, and periodically thereafter" means "obtaining a blood sample from
the patient
in order to perform liver function tests and monitoring liver function after
initiation of
dronedarone administration, monthly for six months, at months 9 and 12, and
periodically thereafter".
Thus, the invention also relates to the regimen to administrate dronedarone to
patients
in a safe and effective way, with a method to manage the risk of liver injury
in patients
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receiving treatment with dronedarone or pharmaceutically acceptable salts
thereof by
performing the following steps:
a) obtaining a blood sample from the patient prior to treatment with
dronedarone,
b) performing liver function tests prior to treatment with dronedarone,
c) initiating dronedarone administration,
d) obtaining a blood sample from the patient in order to perform liver
function tests
and monitoring liver function after initiation of dronedarone administration,
monthly for six months, at months 9 and 12, and periodically thereafter,
and additionally by performing the following steps:
1 0 e) if
alanine aminotransferase (ALT) levels are elevated higher than three times
the upper limit of normal (ULN), re-measuring levels,
f) if confirmed to be greater than three times the upper limit of normal,
withdrawing administration of dronedarone,
g) continuing close observation until normalization of ALT and,
h) investigating the probable cause, including those related to underlying
cardiac
conditions.
According to one embodiment, step d) is performed one week, one month, monthly
for
six months, at months 9 and 12, and periodically after initiation of
dronedarone
administration.
The invention also relates to dronedarone or one of its pharmaceutically
acceptable
salt for use in a safe way in patients with a cardiovascular history,
particularly in
patients with Atrial fibrillation or flutter, more particularly in patients
with paroxysmal or
persistent atrial fibrillation, said use comprising the following steps:
a) obtaining a blood sample from the patient prior to treatment with
dronedarone,
b) performing liver function tests prior to treatment with dronedarone,
c) initiating dronedarone administration,
d) obtaining a blood sample from the patient in order to perform liver
function tests
and monitoring liver function after initiation of dronedarone administration,
monthly for six months, at months 9 and 12, and periodically thereafter.
The invention also relates to dronedarone or one of its pharmaceutically
acceptable
salt for use in a safe way in patients with a cardiovascular history,
particularly in
patients with Atrial fibrillation or flutter, more particularly in patients
with paroxysmal or
persistent atrial fibrillation, said use comprising the following steps:
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a) obtaining a blood sample from the patient prior to treatment with
dronedarone,
b) performing liver function tests prior to treatment with dronedarone,
c) initiating dronedarone administration,
d) obtaining a blood sample from the patient in order to perform liver
function tests
and monitoring liver function after one week and after one month following
initiation of dronedarone administration initiation, monthly for six months,
at
months 9 and 12, and periodically thereafter.
Additionally the use according to the invention comprises the above mentioned
steps e)
to h).
Liver injury may comprise hepatic events such as liver function test
abnormalities and
hepatocellular liver injury, including acute hepatic failure or life-
threatening acute liver
failure.
Liver functions test may comprise determination of liver enzymes levels. These
enzymes may be alkaline phosphatase (ALP, AP), alanine aminotransferase (ALT),
aspartate aminotransferase (AST), total bilirubine.
"Managing the risk" may be defined as "reducing the risk".
The uses and methods according to the invention enable to decrease the risk of
liver
injury, when dronedarone or pharmaceutically acceptable salts or esters
thereof is
administered for treating patients with paroxysmal or persistent atrial
fibrillation (AF) or
atrial flutter (AFL), with a recent episode of AF/AFL and associated
cardiovascular risk
factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular
accident, left atrial
diameter 50 mm or left ventricular ejection fraction [LVEF] <40%), who are in
sinus
rhythm or who will be cardioverted.
The patients concerned by the present invention have a cardiovascular history.
They
may be affected, for example, by a Atrial Fibrillation such as a persistent
Atrial
Fibrillation, a paroxysmal Atrial Fibrillation or a permanent Atrial
Fibrillation or by a
Atrial Flutter.
According to another embodiment, patients are chosen from patients with
paroxysmal
or persistent atrial fibrillation.
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The American College of Cardiology, American Heart Association, and the
European
Society of Cardiology recommend in their guidelines the following
classification system
based on simplicity and clinical relevance:
5
Patients with Paroxysmal Atrial Fibrillation means patients with recurrent
episodes that self-terminate in less than 7 days.
Patients with persistent Atrial Fibrillation means patients with recurrent
episodes that last more than 7 days.
If a first detected episode self-terminates in less than 7 days and then
another
episode begins later on, the case has moved into the category of paroxysmal
AF.
Although patients in this category have episodes lasting up to 7 days, in most
cases of
paroxysmal AF the episodes will self-terminate in less than 24 hours. If
instead the
episode lasts for more than 7 days, it is unlikely to self-terminate and it is
called
persistent AF. In this case, the episode may be terminated by cardioversion.
If cardioversion is unsuccessful or it is not attempted, and the episode is
ongoing for a long time (e.g. a year or more), the patient's AF is called
permanent.
Among the patients having a cardiovascular history according to the invention,
in
particular having a history of atrial fibrillation or atrial flutter, mention
may also be made
of patients also exhibiting at least one additional risk factors, such as:
- age equal to or above 70, or even above 75
- hypertension,
- diabetes,
- prior cerebrovascular disease,
- left atrial
diameter greater than or equal to 50 mm measured by
echocardiography,
- left ventricular ejection fraction less than 40%, measured by two-
dimensional echography.
Among the patients having a cardiovascular history according to the invention,
in
particular having a history of atrial fibrillation or atrial flutter, mention
may also be made
of patients also exhibiting additional risk factors, i.e. at least one
pathologies chosen
from:
- Structural heart disease,
- Lone Atrial Fibrillation,
- Coronary heart disease, and
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- Dilated cardiomyopathy,
and/or at least one cardiac device chosen from:
- Pacemaker, and
- Valvular heart.
Mention may be made that "method to manage the risk of liver injury" may be
understood as
- use of dronedarone or one of its pharmaceutically acceptable salt, for
the
preparation of a drug for use in the prevention of liver injury"
1 0 - use of dronedarone or one of its pharmaceutically acceptable salt,
for the
preparation of a drug for use in the management of the risk of liver injury"
- dronedarone or one of its pharmaceutically acceptable salt for use in the
management of the risk of liver injury,
- dronedarone or one of its pharmaceutically acceptable salt for use in the
prevention of liver injury,
and vice-versa.
Mention may be made that "dronedarone for use in " may be understood as use of
dronedarone for the preparation of a medicament for use in" and vice-versa.
For their therapeutic use, dronedarone and pharmaceutically acceptable salts
thereof
are generally introduced into pharmaceutical compositions.
These pharmaceutical compositions contain an effective dose of dronedarone or
of a
pharmaceutically acceptable salt thereof, and also at least one
pharmaceutically
acceptable excipient.
Said excipients are chosen according to the pharmaceutical form and the method
of
administration desired, from the usual excipients which are known to those
skilled in
the art.
In said pharmaceutical compositions for oral, sublingual, subcutaneous,
intramuscular,
intravenous, topical, local, intratracheal, intranasal, transdermal or rectal
administration, dronedarone, or the salt thereof, can be administered in unit
administration form, as a mixture with conventional pharmaceutical excipients,
to
animals and to humans in the cases mentioned above.
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The suitable unit administration forms comprise forms for oral administration,
such as
tablets, soft or hard gel capsules, powders, granules and oral solutions or
suspensions,
sublingual, buccal, intratracheal, intraocular or intranasal administration
forms, forms
for administration by inhalation, topical, transdermal, subcutaneous,
intramuscular or
intravenous administration forms, rectal administration forms, and implants.
For topical
application, dronedarone and pharmaceutically acceptable salts thereof can be
used in
creams, gels, ointments or lotions.
By way of example, a unit administration form of dronedarone or a
pharmaceutically
acceptable salt thereof, in tablet form, may correspond to one of the
following
compositions (Examples 1 - 4) according to the invention:
EXAMPLE 1
Ingredients mg
Dronedarone hydrochloride (corresponding to 400 mg of 426
base)
Methylhydroxypropylcellulose 21.1
Lactose monohydrate 46.55
Maize starch 45.5
Polyvinylpyrrolidone 65
Poloxamer 407 40
Anhydrous colloidal silica 2.6
Magnesium stearate 3.25
650
EXAMPLE 2
Ingredients mg
Dronedarone hydrochloride (corresponding to 400 mg of 426
base)
Microcrystalline cellulose 65
Anhydrous colloidal silica 2.6
Anhydrous lactose 42.65
Polyvinylpyrrolidone 13
Poloxamer 407 40
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Macrogol 6000 57.5
Magnesium stearate 3.25
650
EXAMPLE 3
Ingredients mg
Dronedarone hydrochloride (corresponding to 400 mg of 426
base)
Microcrystalline cellulose 26
Maize starch 45.5
Polyvinylpyrrolidone 65
Poloxamer 407 40
Anhydrous colloidal silica 3.25
Magnesium stearate 3.25
Lactose monohydrate 41.65
650
EXAMPLE 4
Ingredients mg
Dronedarone hydrochloride (corresponding to 200 mg of 213
base)
Microcrystalline cellulose 13
Maize starch 22.75
Polyvinylpyrrolidone 32.5
Poloxamer 407 20
Anhydrous colloidal silica 1.3
Magnesium stearate 1.625
Lactose monohydrate 20.825
325
The dose of dronedarone administered per day, orally, may reach 800 mg, taken
in one
or more intakes. More specifically, the dose of dronedarone administered may
be taken
with food. For example, the dose of dronedarone administered per day, orally,
may
reach 800 mg, taken in two intakes with a meal.
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The dose of dronedarone administered per day, orally may be taken at a rate of
twice a
day (usually abbreviated BID) with a meal for example with the morning and the
evening meal. More specifically, the two intakes may comprise same quantity of
dronedarone.
Advantageously, the dose of dronedarone administered, orally, may reach 400 mg
BID,
taken together with a meal, for example with the morning and the evening meal.
There may be specific cases where higher or lower dosages are appropriate;
such
dosages do not depart from the context of the invention. According to the
usual
practice, the dosage appropriate for each patient is determined by the
physician
according to the method of administration, the weight, the pathology, the body
surface,
the cardiac output and the response of said patient.
According to another of its aspects, the present invention also relates to a
method for
treating the pathologies indicated above, which comprises the administration,
to a
patient, of an effective dose of dronedarone or a pharmaceutically acceptable
salt
thereof.
The present invention is illustrated by the data hereinafter with reference to
the
attached drawings in which:
Figure 1 represents a Kaplan Meier curve with the cumulative rate of first
hepatic event or ALT greater than or equal to 5 times ULN during the on-
treatment period.
In the pool of 5 placebo controlled studies in patients with AF/AFL
(DRI3550/DAFNE,
EFC4508/ERATO, EFC3153/EURIDIS, EFC4788/ADONIS, EFC5555/ATHENA), the
hepatic events were analyzed with the following selection:
= ALT 5 x ULN, or
= SOC rHepatobiliary disorders', or
= SMQ "Liver related investigations signs and symptoms" using broad and
narrow
selection
The time to onset analysis of these hepatic events showed a trend in which the
dronedarone group had an earlier onset of hepatic events during the first 6
months
compared to placebo (Figure 1).
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After 1 year, the incidences appeared to be similar in the 2 groups, the data
being
entirely driven by adverse events reported in the ATHENA study (enzymes not
routinely collected).
5
In addition, two spontaneously post marketing safety reports of hepatic
failure leading
to liver transplantation were reported in patients treated with MULTAQ
(dronedarone).
CASE 1 : A 69-year-old female patient with normal baseline liver function
tests,
10 experienced acute hepatic failure 4.5 months after starting
treatment with
dronedarone for recurrent re-entry tachycardia (off label indication) and 7
days
after her last dose of dronedarone (reason for drug withdrawal not stated).
She
required a liver transplant and was still in intensive care at the time of the
last
report. Concomitant medications included lisinopril, hydrochlorothiazide,
bisoprolol, amlodipine, levothyroxine, simvastatin, acetylsalicylic acid,
alendronic acid, tiotropium bromide and formoterol. Relevant history included
triple vessel disease coronary artery disease, COPD, skin tumor and
heterozygous Factor V Leiden mutation. Histological examination of the
explanted liver was reported as consistent with a drug-induced toxicity.
CASE 2 : A 72-year-old female patient with medical history of paroxysmal
atrial
fibrillation and SjOgren's syndrome experienced acute hepatic failure almost
six
months after starting dronedarone. She underwent successful liver
transplantation. At the time of the report the patient was recovering and was
still
in the intensive care unit. Liver function tests 3 months prior to dronedarone
start had been within normal limits. Concomitant medications included
metoprolol, amlodipine, omeprazole, warfarin, alprazolam, calcium, biotin and
multivitamins. No evidence for autoimmune hepatitis was found. The liver
histology revealed 60% to 70% necrosis. All details of the histopathology
3 0 evaluation were not available at time of report.
Thus, those events occurred within 6 months after dronedarone treatment
initiation and
consequently support the claimed invention to monitor liver function and risk
of liver
injury.
